Date of Award

5-2007

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

David C. Baker

Committee Members

John F. C. Turner, Michael Best, David Brian

Abstract

3-Phenyl-2,3-dihydro-1,2-benzisothiazole 1,1 dioxide (NSC108406), identified as an HIV-1 reverse transcriptase inhibitor, is chosen for lead optimization. A series of analogues are docked using SYBYL FlexiDock into both wild-type (wt) reverse transcriptase (RT) and Tyr181 --> Cys181 (Y181C) RT, from the dataset of efavirenz (Sustiva®) bound to the enzyme. Minimizations using genetic algorithms are performed, and the lowest energy conformations are evaluated. Five structures emerge as good fits either in both enzymes or only in Y181C RT. 3-(m-Cyclopropylphenyl)- and 3-(isopropylfuranyl)-2-methyl-2,3- dihydro-1,2-benzisothiazole 1,1-dioxides do not exhibit improved binding in wt RT over efavirenz. In the Y181C pocket, the furanyl ring oxygen is oriented towards Cys181, and the cyclopropyl group on the phenyl ring makes a strong contact with Tyr183. Three 3-(alkylethynyl)-2,3-dihydro-2-methyl-1,2-benzisothiazole 1,1-dioxides (ethynyl sultams) make very good contacts in both wt and Y181C RT.

Synthesis of the ethynyl sultams is attempted using the appropriate alkylethynyllithium reagents with saccharin, but 3,3-bisalkylethynyl-2,3-dihydro- 1,2-benzisothiazole 1,1-dioxides are the principal products. These are methylated to give the bisalkylated sultams. When docked into wt RT, they are consistently placed outside the pocket. In Y181C RT they make similar contacts to nevirapine, a first-generation NNRTI.

3-Chloro-1,2-benzisothiazole 1,1-dioxide is then coupled to the alkylethynyllithium reagents to give the desired monosubstituted products. (R,R)-N-(p-tolunesulfonyl)-1,2-diphenylethylenediamine-rhodium- (pentamethycycopentadienyl)-Cl [(R,R)-TSDPEN-Rh-Cl], an enantioselective catalyst for the reduction of imines, is used in an attempt to produce optically active sultams; however, the products are not optically active. The cyclopropyland cyclobutylethynyl bonds are reduced to the corresponding alkanes. These new cycloalkylethyl sultams, when docked into RT, exhibit a better fit in Y181C than wt RT, similar to that of efavirenz.

In a study on the mechanism of the enantioselective reduction of 3-alkylor aryl-imines by (R,R)-TSDPEN-Rh-Cl, a number of imines are docked into the catalyst cavity in two different approaches using the “original” approach that gives the observed enantioselectivity and the “reverse” approach, which is thought to give the opposite enantiomer. Molecular dynamic studies are carried out. In all 3-(aryl/alkyl)imine sultams, an average of at least 10 kcal/mol energy difference is observed between both approaches, showing probable structures for the intermediate complex in the catalytic cycle that accounts product stereochemistry.

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